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| United States Patent |
5,091,539
|
|
Makisumi
, et al.
|
February 25, 1992
|
Azolyl cycloalkanol derivatives and agricultural fungicides
Abstract
Novel 1-substituted -2-imidazolyl (or 1,2,3-triazolyl)cyclohexanols or
cycloheptanols having anti-fungal activity against wide range of
agricultural fungi with vapor effect.
| Inventors:
|
Makisumi; Yasuo (Hyogo, JP);
Murabayashi; Akira (Osaka, JP);
Hatta; Takayuki (Shiga, JP);
Ishiguro; Takeo (Shiga, JP)
|
| Assignee:
|
Shionogi & Co., Ltd. (Osaka, JP)
|
| Appl. No.:
|
531347 |
| Filed:
|
May 31, 1990 |
Foreign Application Priority Data
| Feb 03, 1984[JP] | 59-18564 |
| Feb 15, 1984[JP] | 59-27905 |
| Current U.S. Class: |
548/267.8; 548/262.2; 548/266.2; 548/266.6; 548/315.1; 548/345.1 |
| Intern'l Class: |
C07D 249/08; C07D 233/60 |
| Field of Search: |
548/262.2,341,336,267.8
|
References Cited
U.S. Patent Documents
| 3636002 | Jan., 1972 | Godefrai et al. | 260/309.
|
| 4079062 | Mar., 1978 | Van Reet et al. | 548/262.
|
| 4289526 | Sep., 1981 | Worthington et al. | 71/92.
|
| 4380546 | Apr., 1983 | Sanfer et al. | 548/268.
|
| 4414210 | Nov., 1983 | Miller et al. | 568/645.
|
| 4431815 | Feb., 1984 | Thorogood | 548/335.
|
| 4503062 | Mar., 1985 | Gravestock | 548/262.
|
| 4554007 | Nov., 1985 | Funaki et al. | 514/383.
|
| Foreign Patent Documents |
| 722813 | Apr., 1969 | BE.
| |
| 0011770 | Jun., 1980 | EP.
| |
| 015639 | Sep., 1980 | EP.
| |
| 0019359 | Nov., 1980 | EP.
| |
| 2244761 | Mar., 1974 | DE.
| |
| 2654890 | Jun., 1977 | DE.
| |
| 2370432 | Jun., 1978 | FR.
| |
| 1445707 | Aug., 1976 | GB.
| |
| 1464224 | Feb., 1977 | GB.
| |
Other References
Il Farmaco, Edizione Scientifica, Anno XXVI, No. 11, Nov., 1971, pp.
931-940.
|
Primary Examiner: Morris; Patricia L.
Attorney, Agent or Firm: Wenderoth, Lind & Ponack
Parent Case Text
This application is a division of application Ser. No. 229,790, filed Aug.
4, 1988, now abandoned, which application is a continuation of now
abandoned application Ser. No. 022,067, filed Mar. 5, 1987, which
application is, in turn, a continuation of now abandoned application Ser.
No. 696,432, filed Jan. 30, 1985.
Claims
What we claim is:
1. A process for preparing a compound of the formula I:
##STR8##
wherein R is alkyl, phenyl, benzyl, thienyl or naphthyl, which groups are
unsubstituted or are substituted by one or more halogens, Y is methine or
nitrilo and n is 2 or 3 with the proviso that azolyl and hydroxy are in
cis configuration when R is phenyl or halogenophenyl, or an acid addition
salt thereof which comprises reacting a cycloalkane of the formula II
##STR9##
wherein Y and n are each as defined above with a compound of the formula
III;
RZ III
wherein Z is a halomagnesium or an alkali metal and R is the same as
defined above to obtain the cis-isomer of the compound of formula I as the
main product.
Description
BACKGROUND OF THE INVENTION
Some triazolylalkanols are known to be effective as agricultural fungicides
(British Patent Publication A-1464224). The European Patent Publication
No. A.sub.1 -0094146 discloses that 1-phenyl (or substituted
phenyl)-2-imidazolyl (or triazolyl)cycloalkanol derivatives are generally
active against fungi. In the derivatives, the neighboring azolyl and
hydroxy may be positioned in cis or trans configuration. The latter
specification, however, discloses only a process which is supposed to give
trans-isomers as the main product when deduced from reaction mechanism.
The compounds shown in the working examples are recognized as
trans-isomers from the physical constants. Furthermore, the specification
refers to none of the differences in anti-fungal activity caused by the
difference of the configuration between cis and trans forms. Especially,
it does not suggest the specificity of the cis-isomer of the present
invention.
SUMMARY OF THE INVENTION
This invention relates to azolylcycloalkanol derivatives, the salts and the
process for preparing the same. Further, it relates to an agricultural
fungicide containing the above compound as active ingredient.
This invention includes novel imidazolyl- or triazolyl-cycloalkanols having
an alkyl, aralkyl or heterocyclic ring group at the 1 position, of which
strong anti-microbial, especially anti-fungal activity is not known.
Further, cis-1-phenyl (or substituted phenyl)-2-imidazolyl (or
triazolyl)-cycloalkanols are not known to have anti-fungal activity
against wide range of agricultural fungi with vapor effect.
The objective compounds of this invention are represented by the formula I:
##STR1##
wherein R is alkyl, phehyl, benzyl, thienyl or naphthyl, being optionally
substituted by one or more halogens, Y is methine or nitrilo and n is 2 or
3 with the proviso that azolyl and hydroxy are in cis configuration when R
is phenyl or halogenophenyl.
DETAILED EXPLANATION OF THE INVENTION
This invention includes 1-substituted-2-imidazolyl- (or
1,2,4,-triazol-1-yl)cyclohexanols and cycloheptanols.
The compounds I may take the cis and trans configuration as noted above. In
this specification, the trans and cis isomers are decided in the relation
of the hydroxy at the position 1 and the azolyl at the position 2. This
invention includes cis-isomers and trans-isomers as well as both
enantiomers except for the trans-isomers of the compounds I of which R is
phenyl or halogenophenyl. Additionally, this invention includes the salts
of the compounds I, for example, salts with an inorganic acid (e.g.
hydrochloride, hydrobromide, hydroiodide, and phoshate) and salts with an
organic acid (e.g. acetate, citrate, maleate, malate, succinate,
tartarate, cinnamate and benzoate).
In the above definition, alkyl means C.sub.1 to C.sub.5 straight or
branched alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
t-butyl, pentyl, isopentyl and the like. Halogen includes fluorine,
chlorine, bromine and iodine.
Thus, the group R in the compounds I may be alkyl, halogenoalkyl, phenyl,
haogenophenyl, thienyl, halogenothienyl, naphthyl or halogenonaphthyl with
the proviso that the group R and hydroxy form the cis configuration when R
is phenyl or halogenophenyl. The halogen may be located at any position of
the group R and the number of halogens is not limited. Preferable R is,
for example, 2-chlorophenyl, 2-fluorophenyl, 3-chlorophenyl,
4-chlorophenyl, 4-fluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,
3,4-dichlorophenyl, benzyl, 2-chlorobenzyl, 4-chlorobenzyl,
2,4-dichlorobenzyl, 4-fluorobenzyl, 2,4-difluorobenzyl, 2-thienyl,
5-chloro-2-thienyl, 5-iodo-2-thienyl, 3,5-dichloro-2-thienyl,
3,4,5-trichloro-2-thienyl, 1-naphthyl and the like. The more preferable R
groups are, for example, 2-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl,
2,5-dichlorophenyl, 5-chloro-2-thienyl, 3,4,5-trichloro-2-thienyl,
naphthyl and the like. Y is methine or nitrilo and nitrilo is preferable.
The compounds I are prepared by several processes and the main product may
be in cis-form or trans-form depending on the process. The process for
preparing each isomer is shown below. In the following scheme, cis-or
transisomer alone is illustrated without referring to the enantiomer to be
produced at the same time, which should not be construed that the other
enantiomer is not produced.
PROCESS (1)
##STR2##
(wherein Z is halomagnesium or an alkali metal and R, Y and n each has the
same significance as noted above.)
The process consists of introduction of the substituent R into the position
1 of a cycloalkanone of the formula II to give a cycloalkanol (Ia);
namely, reaction of a Compound II with a Grignard reagent or an alkali
metal compound of the above formula III having a desired substituent to
give cisisomer (Ia) as main product.
It is practised in an ether solvent (e.g. tetrahydrofuran, diglyme, ether
or isopropyl ether) or in a mixed medium such as benzene slovent (e.g.
benzene or toluene) containing an ether solvent. The ether solvent alone
is preferably used as reaction medium. The reaction is generally practised
under cooling.
Among the starting compounds II, (1,2,4-triazol-1-yl)cyclohexanone is a
known compound disclosed in the British Patent Publication No. 1464224-A.
Other Compounds II can be easily prepared as shown by the following
reaction scheme.
##STR3##
(wherein M is hydrogen or an alkali metal and Y and n each has the same
significance as noted above).
The reaction of cycloalkene oxide (V) with imidazole, 1,2,4-triazol or its
alkali salt (e.g. sodium or potassium salt) of the formula VI is effected
in a solvent or without solvent at room temperature or under heating to
give 2-azolylcycloalkanol (IV). As the reaction solvent, polar organic
solvents are preferable. They are, for example, alcohols (e.g. methanol,
ethanol, propanol and isopropanol), dimethylformamide, dimethylacetamide
and the like. Dimethylformamide and dimethylacetamide are favorable when
Compound VI is an alkali metal salt. The reaction may be effected in the
presence of a Lewis acid when Compound VI is a free base.
The resulting Compound IV is oxidized to give the desired
2-azolylcycloalkanone (II). The oxidation is effected, for example, by the
reaction with an acid anhydride (e.g. trifluoroacetic anhydride or acetic
anhydride) or oxalyl chloride and dimethylsulfoxide in methylene chloride
followed by treatment with an organic base (e.g. triethylamine or
pyridine).
The thus prepared compound is separated and purified by the usual methods
such as extraction, recrystallization, chromatography and the like and
made in to a desired salt, if necessary.
PROCESS (2)
The process for preparing a trans-isomer as main product is mostly effected
in the nearly the same manner as that disclosed in the European Patent
Publication No. A.sub.1 -0094146 as shown below.
##STR4##
(wherein X' is bromine or chlorine and R, Y, n and M each represents the
same significance as noted above).
(i) As shown in the above scheme, 1-substituted cycloalkene oxide (VII) is
made to react with imidazole, 1,2,4-triazole or its salt (e.g. sodium or
potassium salt) without solvent or in a medium such as an alcohol solvent
(e.g. methanol, ethanol, propanol or isopropanol), dimethylformamide,
dimethylacetamide or the like at room temperature or under heating. The
reaction can be effected under the same condition as in that of the
above-noted Compound V with Compound VI.
(ii) Cycloalkane halohydrin (VIII) is made to react with Compound VI in an
inactive organic solvent (e.g. dimethylformamide or dimethylacetamide) at
room temperature or under heating, preferablly at about 20.degree. to
about 100.degree. C. The reaction may be effected in the presence of an
acid condensing agent if Compound VI is a free base, i.e. imidazole or
triazole. As the acid condensing agent, an excess amount of Compound VI
can be used or an organic base (e.g. pyridine or triethylamine) can be
added to the reaction mixture.
The starting compound VII and VIII can be prepared from cyclohexanone or
cycloheptanone as shown below.
##STR5##
(wherein R, n and X' each has the same significance as noted above).
Cycloalkanone (XI) is subjected to the similar Grignard reaction as noted
in the above (1) and the resulting tertiary alcohol (X) is applied to
dehydration, e.g. by heating with a catalysis (e.g. p-toluenesulfonic
acid) to give 1-substituted cycloalkene (IX). Successively, Compound IX is
oxidized with a peracid (e.g. m-chloroperbenzoic acid, perbenzoic acid,
performic acid or peracetic acid) to give cycloalkene oxide (VII).
Alternatively, Compound IX is converted into halohydrin to give
cycloalkane halohydrin (VIII). Compound IX, for example, is made to react
with N-bromoacetamide (NBA), N-bromosuccinimide (NBS) or
N-chlorosuccinimide (NCS) in an aqueous solvent (e.g. aqueous acetone,
aqueous dimethylsulfoxide, aqueous tetrahydrofuran or aqueous dioxane)
under cooling or at room temperature or reacted with bromine/potassium
bromide in water to give Compound VIII. Compound VIII can be prepared by
reaction of Compound VII with hydrogen halide.
The desired Compound I can be prepared by the above processes alone while
halogenated Compound I can also be prepared by halogenation of
non-halogenated Compound I obtained by the above processes.
The thus prepared compound is separated and purified by the usual methods
such as extraction, recrystallization, chromatography and the like and
made into a desired salt, if necessary.
The compound I and the salts have strong anti-microbial activity,
especially against fungi infecting agricultural products and are useful as
fungicides for agricultural products, seeds, seedlings and the like. The
anti-fungal activity against typical agricultural fungi is shown below. In
the following tests, the test compounds are represented by the numbers
used in the working examples.
TEST 1
Control Test to Damping-Off of Cucumber
(1) The fungus causing damping-off of cucumber seedlings, Rhizoctonia
solani or Fusarium oxysporum was cultured on a wheat bran medium at
28.degree. C. for 5 days, which was mixed with sterilized soil and
cultured for 2 days to prepare the inoculum. Sterilized soil (150 g) was
put into a pot of 9 cm in diameter. The surface of the spot was covered
with the above inoculum. A solution (30 ml) at a concentration of 500 ppm
or 31.3 ppm the test compound was poured into each pot, which was then
dried. Twenty cucumber seeds (Cultivar: Matsukaze) were sown 2 days after.
The pots were kept at 30.degree..+-.2.degree. C. for 14 days. The
infection was observed 14 days after and disease degree and percent
disease degree were obtained by setting an evaluation index for each
disease sympton.
(2) Evaluation
##EQU1##
wherein a: number of seeds without germination
b: number of seedlings showing damping-off
c: number of wilted seedlings
d: number of seedlings being a little brownish in cotyledons or at the
bottom of the stem
e: number of uninfected seedlings
##EQU2##
wherein a: number of seeds without germination or seedlings with
damping-off
b: number of wilted seedlings
c: number of seedlings being a little brownish in cotyledons or at the
bottom of the stem
d: number of uninfected seedlings
##EQU3##
(3) Results
TABLE 1
______________________________________
Fusarium
oxysporum
Rhizoctonia solani
Dis- Percent
Concen- Percent Dis-
ease Disease
Test tration Disease ease Control
De- Control
Comp. (ppm) Degree (%) gree (%)
______________________________________
12 500 0 100 17 83
13 500 5 95 100 0
28 31.3 8 92 -- --
30 31.3 18 82 -- --
32 31.3 10 90 -- --
Captan 800 -- -- 0 100
Mepronil
750 5 95 -- --
" 47 77 23 -- --
Untreated
-- 100 0 100 0
______________________________________
TEST 2
Control Test of Botrytis Rot (Gray Mold) of Cucumber
(1) Seedlings of cucumber (Cultivar: Matsukaze) were planted in a pot of 9
cm in diameter. The first leaf was sprayed with 3 ml each of solutions
containing the test compound at the concentration of 125 or 31.3 ppm and
the plant was dried by the air. After inoculation of the spores of
Botrytis cinerea, the plants were kept at 20.degree..+-.2.degree. C. and
90-100% humidity ((i) protective spraying). Alternatively, the spores were
inoculated at first and when the leaves suffered a little (about 2 days
after), the solutions of the test compounds were sprayed ((ii) curative
spraying). Evaluation was practised 3 days after the inoculation. Percent
disease control was calculated by the ratio of diameter of diseased area
in treated and untreated plants.
(2) Evaluation
##EQU4##
(3) Results
TABLE 2
______________________________________
Concen- Percent Disease Control
Test tration Protective Curative
Compound (ppm) Spraying Spraying
______________________________________
13 125 100 94
22 125 100 89
31.3 100 46
24 125 100 94
31.3 100 86
28 125 100 79
31.3 40 48
30 125 100 94
31.3 89 86
Iprodione 125 100 90
31.3 100 64
Untreated -- 0 0
______________________________________
TEST 3
Control Test to Sclerotinia Rot of Cucumber
(1) This test was practised in the same manner as in the above test,
control test of Botrytis rot (gray mold) of cucumber, except for using the
mycelium of Sclerotinia sclerotiorum as inoculm.
(2) Evaluation
The same as in test 2.
(3) Results
TABLE 3
______________________________________
Concen- Percent Disease Control (%)
Test tration Protective Curative
Compound (ppm) Spraying Spraying
______________________________________
13 125 100 95
22 125 100 95
31.3 67 93
24 125 100 97
31.3 100 96
28 125 80 97
31.3 56 77
30 125 100 96
31.3 89 94
32 125 100 94
31.3 72 86
Iprodione 125 100 90
31.3 100 77
Untreated -- 0 0
______________________________________
TEST 4
Control Test to Powdery Mildew of Cucumber
(1) Seeds of cucumber (Cultivar: Matsukaze) were sown in a pot of 9 cm in
diameter and the pots were kept in a green house until the plant was grown
for 2-3 leaf stage. The first leaf was sprayed with, (i) 3 ml each of
solutions containing the test compound at the prescribed concetrations and
dried by the air (foliar treatment). Inoculation of spore suspension of
Sphaerotheca fuliginea by spraying was practised 2 days before the
treatment (curative effect) or 1 day after the treatment (protective
effect). Alternatively, (ii) 5 ml of the solution was applied at the root
of the seedlings (soil treatment). The pots were kept in a greenhouse for
2 days and inoculation was practised in the same manner noted above. (iii)
After sprayed with 3 ml of a solution of the test compound at a
concentration of 125 ppm and dried by the air, the treated pots were set
in a greenhouse. Untreated pots were placed next to the treated pots.
Those treated and untreated plants were inoculated with spore suspension.
Protective effect of the test compounds by vapor was thus checked. The
effect was examined 14 days after the inoculation of the spores.
(2) Evaluation
The results of both foliar and soil treatments were represented by the
following index.
0: Disease sign is observed on the whole leaf.
3: Disease sign is observed on the leaf in about 50%.
5: Disease sign is observed on the leaf in about 30%.
7: Disease sign is observed on the leaf in about 20%.
9: a little disease sign is observed.
10: No sign is observed.
Vapor effect is shown by positive (+) or negative (-), 9-10 and 0-3 in the
above index respectively.
(3) Results
TABLE 4
______________________________________
Concen- Protective Index
Test tration Foliar Soil Vapor
Compound (ppm) Treatment Treatment
Effect
______________________________________
1 125 10 5 +
3 125 10 10 +
5 125 10 3 +
6 125 10 0 -
12 125 10 10 +
13 125 10 10 +
Chinome- 125 10 - -
thionat
Dimethirimol
500 -- 5 -
Untreated -- 0 0 -
______________________________________
TABLE 4
______________________________________
Soil
Cencen- Foliar Treatment
Treatment
Test tration Protective
Curative
Protective
Compound (ppm) Effect Effect Effect
______________________________________
22 31.3 10 10 10
7.8 10 10 10
2.0 10 10 5
0.5 5 10 0
23 31.3 10 10
7.8 10 10
2.0 5 3
0.5 0 0
24 31.3 10 10 10
7.8 10 10 10
2.0 10 10 0
0.5 5 10 0
26 31.3 10 10
7.8 9 9
2.0 3 7
0.5 0 0
27 31.3 10 10
7.8 9 10
2.0 3 5
0.5 0 0
28 31.3 10 10 10
7.8 10 10 10
2.0 5 9 5
0.5 0 5 0
29 31.3 10 10
7.8 9 9
2.0 3 3
0.5 0 0
30 31.3 10 10 10
7.8 10 10 10
2.0 9 10 0
0.5 0 7 0
31 31.3 10 10
7.8 9 10
2.0 0 9
0.5 0 3
32 31.3 10 10 10
7.8 10 10 10
2.0 9 10 0
0.5 0 7 0
33 31.3 10 10 0
7.8 10 10 0
2.0 5 10 0
0.5 0 3 0
34 31.3 10 10 0
7.8 9 10 0
2.0 0 10 0
0.5 0 5 0
35 31.3 10 10 10
7.8 10 10 9
2.0 10 10 0
0.5 5 10 0
Triadime-
31.3 10 10 10
fon 7.8 9 10 3
2.0 7 9 0
0.5 0 0 0
Untreated
-- 0 0 0
______________________________________
TEST 5
Control Test of Crown Rust of Oat
(1) Young oats (Cultivar: Pc38) grown in pots in a greenhouse were (i)
sprayed with 10 ml each of solution of the test compounds at a prescribed
concentration and after air-drying, they were inoculated with 15 mg of
uredospores of Puccinia coronata per 20 pots (protective spraying) or (ii)
sprayed with the test solution 3 days after inoculation of uredospores.
After each plant was kept at 20.degree.-25.degree. C. in a greenhouse for
2 weeks, number of uredia was counted on the first leaf.
(2) Evaluation
##EQU5##
(3) Result
TABLE 5
______________________________________
Concen- Percent Disease Control
Test tration Protective Curative
Compound (ppm) Spraying Spraying
______________________________________
1 125 100 100
22 50 100 100
25 100 88
12.5 100 64
Triadimefon
125 100 100
Fenarimol 50 100 98
25 89 92
12.5 62 75
Untreated -- 0 0
______________________________________
TEST 6
Control Test to Powdery Mildew of Cucumber by Vapor
(1) The first leaves of young cucumber (Cultivar: Matsukaze) planted in pot
of 9 cm in diameter were inoculated with spore suspension of Sphaerotheca
fuliginea. After the plants were kept in a greenhouse for 2 days, thin
cover plates, 15 mm in diameter, were put on the first leaves. Filter
paper disks soaked with 80 .mu.l of test solution at a concentration of
31.3, 7.8, 2.0 or 0.5 ppm were put on the plates for 3 days. Disease
degrees were observed 14 days after the inoculation.
(2) Evaluation
It is evaluated as + when an inhibition zone was observed around the plate,
as .+-. when the inhibition zone has nearly the same diameter (8 mm) as
that of plate or as - when there is no inhibition zone.
(3) Results
TABLE 6
______________________________________
Concen- Protective
Test tration Effect by
Compound (ppm) Vapor
______________________________________
22 31.3 +
7.8 +
2.0 -
0.5 -
30 31.3 +
7.8 +
2.0 -
0.5 -
Triadimefon 31.3 -
7.8 -
2.0 -
0.5 -
0.5 -
Untreated -- -
______________________________________
TEST 7
Anti-Fungal Activity in vitro
(1) Each test compound was diluted by two-fold dilution with GY medium (2%
glucose and 0.4% yeast extract) containing 0.01% Tween 80 (trademark).
Every diluted solution was inoculated with spore suspension (10.sup.5-5
spores/ml) of Alternaria kikuchiana or a hyphae disk with agar (4 mm in
diameter) of other fungi and incubated at 28.degree. C. for 2 days.
(2) Evaluation
The growth of hyphae was observed with the naked eye and the minumum
inhibition concentrations were obtained.
TABLE 7
______________________________________
Test
Compound
MIC (.mu.g/ml)
Test Fenari-
Fungus 12 22 24 32 mol
______________________________________
Monilinia fructicola
1.56 0.78 0.2 0.39 3.13
Cochiobolus sativus
3.13 6.25 6.25 3.13 1.56
Pyrenophora graminea
6.25 12.5 12.5 1.56 12.5
Diaporthe citri
3.13 12.5 25.0 3.13 >50.0
Ustilago nuda 6.25 12.5 1.56 3.13 25.0
Corticium rolfsii
1.56 >50.0 50.0 12.5 25.0
Alternaria kikuchiana
25.0 50.0 12.5 3.13 6.25
Vasla ceratosperma
3.13 ND ND ND 12.5
Cladosporium herbarum
ND 6.25 6.25 1.56 >50.0
______________________________________
ND: Not Done
TEST 8
Comparative Test of cis- and trans-isomers
Each cis- and trans-isomers of
1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)cyclohexanol (Compound 22 and the
trans-isomer)) and 1-(4-fluorophenyl)-2-(1,2,4-triazol-1-yl)cyclohexanol
(Compound 28 and the trans-isomer) are subjected to control test to
powdery mildew of cucumber and to Borytis rot (gray mold) of cucumber.
Each cis isomer has about 4-16 times more effective than the corresponding
trans isomer as shown in Table 8.
(1) Test methods and evaluation are the same as those in Tests 2, 4 and 6.
(2) Results
The results are shown in Table 9.
TABLE 9
__________________________________________________________________________
Control Test of Powdery Mildew
Control Test of Gray Mold
Test Soil Percent Disease Control
Item Concen-
Foliar Treatment
Treatment Concen-
(%)
Test tration
Protective
Curative
Protective
Vapor
ration
Protective
Curative
Compound
(ppm)
Effect
Effect
Effect
Effect
(ppm)
Spraying
Spraying
__________________________________________________________________________
22 31.3 10 + 125 78 82
7.8 10 .+-.
31.3 62 88
2.0 10 10 10 - 7.8 35 20
0.5 10 10 0
0.12 9 10
0.03 0 9
Trans-isomer
31.3 5 - 125 3 2
of Compound
7.8 0 - 31.3 3 0
22 2.0 10 9 0 - 7.8 0 0
0.5 3 5 0
0.12 0 0
0.03 0 0
28 31.3 10 + 125 80 98
7.8 10 .+-.
31.3 70 92
2.0 10 10 9 - 7.8 17 30
0.5 5 10 0
0.12 0 7
0.03 0 0
Trans-isomer
31.3 9 - 125 0 9
of Compound
7.8 0 - 31.3 5 0
28 2.0 0 9 0 - 7.8 3 0
0.5 0 0 0
0.12 0 0
0.03 0 0
__________________________________________________________________________
As shown above, the compounds (I) of this invention and the salts have
extremely strong anti-fungal activity and are useful as agricultural and
industrial fungicides.
The compounds I are formulated into an anti-fungal composition for
agricultural use comprising as active ingredient about 0.01 to about 90
weight percent of Compound I based on the weight of the composition by
mixing with a suitable solid or liquid carrier and other suitable
adjuvants such as surfactants, diluents, spreaders, synergists, sticker,
dispersant and the like. Solid carriers include talc, clay, bentonite,
pyrophyllite, kaolin, diatomaceous earth, silica and the like. Liquid
carriers include water, methanol, ethanol, acetone, dimethyl formamide,
ether, benzene, xylene, toluene, naphtha and the like. Surfactants include
non-ionic surfactants (e.g. polyoxyethylene alkyl phenyl ethers and
polyoxyethylene fatty acid esters), anionic surfactants (e.g. alkylbenzene
sulfonic acid salts, lignin sulfonic acid salts and dinaphthylmethane
sulfonic acid salts) and the like. As stickers, polyvinyl alcohols, CMC,
gum arabic and the like may be used.
The anti-fungal composition is formulated into powders, wettable powders,
granules, emulsifiable concentrates, suspensions, solutions, fumigants,
gases, pastes and the like and is used for sterilizng agricultural
products, seedlings, seeds and the like as well as soil. The compounds I,
for example, are homogeneously dissolved in a hydrocarbon or an alcohol
with a suitable surfactant to give an emulsifiable concentrate or a
solution. They are mixed with a mineral powder and with a suitable
surfactant, crushed and homogenized to fine powder to give a wettable
powder. The thus-prepared composition is diluted with water to a desired
concentration and applied. Alternatively, it may be diluted with mineral
powder, homoeneously crushed, blended and used as a dust. Finally, the
composition is diluted to contain an effective amount of Compound I.
Besides, the composition can be combined with other agrochemicals, e.g.
insecticides, sterilizers, herbicides, plant-growth regulators, miticides
and the like. It also can be mixed with nutrients.
The composition can be used at a lower concentration compared with the
fungicides on the market as recognized in the above tests. The
concentration is, for example, about 10 to about 1000 ppm, preferably
about 5.0 to about 500 ppm, when used for protective or curative spraying.
The compounds I can be applied by soaking the above composition to a
suitable material such as paper, rope and cloth and putting them around
plants because of the vapor effect.
Additionally, the composition containing a Compound I may be used as an
industrial sterilizer for, for example, painting, timber, paper, cloth and
the like. One example is that an effective amount of Compound I may be
mixed in a paint for a ship to prevent adhearence of shellfish and algae.
A sterilizer containing Compound I at an effective concentration may be
sprayed on or soaked into wall-paper and wall-cloth.
The following examples are included merely to aid in the understanding of
the invention and variations may be made by one skilled in the art without
departing from the spirit and scope of the invention. The term THF means
tetrahydrofuran in the following examples.
EXAMPLE 1
To a Grignard reagent prepared by adding a solution of
.alpha.-bromonaphthalene (814 mg) in anhydrous ether (10 ml) to magnesium
(110 mg), a solution of 2-(1,2,4-triazol-1-yl)cyclohexanone (Compound IIb)
(500 mg) in anhydrous THF (10 ml) was added dropwise with stirring under
ice-cooling. The mixture was stirred at room temperature for 1 hour. After
evaporation of the THF, water was added to the residual solution, which
was then extracted with chloroform. The extract was washed with water,
dried and evaporated. The resultant residue was applied to column
chromatography on silica gel (15 g). From the chloroform-ether (1:1)
fraction, cis-1-(1-naphthyl)-2-(1,2,4-triazol-1-yl)/cyclohexanol, (1) (395
mg) was obtained: mp. 146.degree.-147.degree. C. (ether).
EXAMPLE 2
To a Grignard reagent prepared by adding a solution of p-chlorobenzyl
chloride (1.5 ml) in anhydrous ether (10 ml) to magnesium (220 mg), a
solution of Compound IIb (1.0 g) in anhydrous THF (10 ml) was added
dropwise under ice-cooling. The mixture was stirred at room temperature
for 1 hour. Water was added to the mixture, which was then extracted with
chloroform. The extract was washed with water and evaporated. The
resultant residue was applied to column chromatography on silica gel (30
g). From the ether fraction,
cis-1-(4-chlorobenzyl)-2-(1,2,4-triazol-1-yl)cyclohexanol (2) (760 mg) was
obtained: mp. 49.degree.-51.degree. C. (ether-hexane).
NMR: .delta.(CDCl.sub.3) (J=Hz) 4.17d-d (J=12, 4), 4.03s
Anal. Calcd. for C.sub.15 H.sub.18 N.sub.3 OCl: C, 61.75; H, 6.22; N,
14.40; Cl, 12.15 (%). Found: C, 61.38; H, 6.21; N, 14.07; Cl, 12.33 (%).
EXAMPLE 3
To a Grignard reagent prepared by adding a solution of 2,4-dichlorobenzyl
chloride (0.8 ml) in anhydrous ether (10 ml) to magnesium (80 mg), a
solution of Compound IIb (500 mg) in anhydrous THF (10 ml) was added
dropwise under ice-cooling. The mixture was stirred at room temperature
for 40 minutes. Water was added to the mixture, which was then extracted
with chloroform. The extract was washed with water and evaporated. The
resultant residue was applied to column chromatography on silica gel (15
g). From the ether fraction,
cis-1-(2,4-dichlorobenzyl)-2-(1,2,4-triazol-1-yl)cyclohexanol (3) (367 mg)
was obtained: mp. 129.degree.-130.degree. C. (ether-hexane).
NMR: .delta.(CDCl.sub.3) 4.30d-d (J-12.4), 3.73s
Anal. calcd. for C.sub.15 H.sub.17 N.sub.3 OCl.sub.2 : C, 55.23; H, 5.25;
N, 12.88; Cl, 21.74 (%). Found: C, 55.11; H, 5.22; N, 12.76; Cl, 21.69
(%).
EXAMPLE 4
To a Grignard reagent prepared by adding a solution of
2,6-dichlorothiophene (24.07 g) in anhydrous THF (100 ml) to magnesium
(3.2 g) dropwise, a solution of Compound IIb (20.0 g) in anhydrous THF
(150 ml) was added dropwise under ice-cooling for 30 minutes. The mixture
was stirred at room temperature for 5 hours. Water was added to the
mixture, which was then acidified with 5% hydrochloric acid, successively
neutralized with 5% potassium carbonate and extracted with chloroform. The
extract was washed with water and evaporated. The resultant residue was
applied to column chromatography on silica gel (150 g). From the
chloroform and chloroform-methanol (100:1) fractions,
cis-1-(5-chloro-2-thienyl)-2-(1,2,4-triazol-1-yl)cyclohexanol (4) (16.65
g) was obtained: mp. 150.degree.-151.degree. C. (ether).
NMR: .delta.(CDCl.sub.3) 4.4d-d (J=12, 4), 5.17s, 1H.
EXAMPLE 5
(1) Cycloheptene (10 g) was dissolved in methylene chloride (400 ml) and
85% m-chloroperbenzoic acid (23 g) was portionally added with stirring
under ice-cooling. The mixture was stirred for 10 hours under ice-cooling
and at room temperature for 3 hours. The precipitated benzoic acid was
filtered off and washed with methylene chloride. The filtrate and the
washings were combined and washed with an aqueous solution of sodium
thiosulfate, 5% potassium carbonate and water successively. After drying
the evaporation of methylene chloride gives cycloheptene oxide (Vb) as
oil.
To the product were added propanol (25 ml) and 1,2,4-triazole (8.6 g). The
mixture was heated for 4 hours at 100.degree. C. and the propanol was
removed by evaporation. After addition of a small amount of water, the
residue was extracted with chloroform. The extract was washed with a small
amount of water, dried, and evaporated. The resultant residue is
recrystallized from ether-hexane to give
2-(1,2,4-triazol-1-yl)cycloheptanol (IVd) (13.3 g) (Yield: 35.8%), Mp.
85.degree.-86.degree. C.
NMR: .delta.(CDCl.sub.3) 1.6-2m 10H, 4(br) 2H, 5.0s 1H, 7.73s 1H, 8.03s 1H.
(2) A solution of dimethylsulfoxide (1.05 g) in methylene chloride (10 ml)
was cooled to -78.degree. C. and a solution of trifluoroacetic anhydride
(1.65 ml) in methylene chloride (4 ml) was added dropwise thereto. The
mixture was stirred for 1 hour under cooling. A solution of Compound IVd
(1.63 g) in methylene chloride (18 ml) was added dropwise thereto and the
mixture was made to react at -78.degree. C. to room temperature for 1.5
hours and then cooled to -65.degree. C. Triethylamine (3.75 ml) was added
thereto and the mixture was stirred at -65.degree.-0.degree. C. for 1
hour. The reaction mixture was made alkaline with 5% potassium hydroxide
and extracted with methylene chloride. The extract was washed with water,
dried and evaporated. The residue was applied to column chromatography on
silica gel (30 g). From chloroform-methanol (100:1) fraction,
1-(1,2,4-triazol-1-yl)cyclohepatanone (IId) (1.16 g) was obtained (yield
72%). Mp. 82.degree.-82.5.degree. C. (ether-hexane).
IR: .nu..sub.max (CHCl.sub.3) 1720 cm.sup.-1.
NMR: .delta.(CDCl.sub.3) 1.5-2.3m 8H, 2.65m 2H, 5.28d-d (J=12, 5) 1H, 7.91s
1H, 8.22s 1H.
(3) To a Grignard reagent prepared from anhydrous ether (10 ml), magnesium
(150 mg) and p-chlorobenzyl chloride (966 mg) was added a solution of
Compound IId (538 mg) prepared in (2) in THF (10 ml) with stirring under
ice-cooling. The mixture was made to react at room temperature for 1 hour
and after addition of water, was extracted with chloroform. The extract
was washed with water, dried and evaporated. The resultant residue was
applied to column chromatography on silica gel (15 g). From the ether
fraction, cis-1-(4-chlorobenzyl)-2-(1,2,4-triazol-1-yl)cycloheptanol (5)
was obtained as crystal (yield 75%). Mp. 111.degree.-112.degree. C.
(ether-hexane).
NMR: .delta.(CDCl.sub.3) 1.63 m 10H, 2.42q (J=14) 2H, 3.63s 1H, 4.23d-d
(J=12, -1) 1H, 7.01d (J=9) 2H, 7.22d (J=9) 2H, 7.95s 1H, 8.20s 1H.
Anal. Calcd. for C.sub.16 H.sub.20 NOCl: C, 62.84; H, 6.59; N, 13.74; Cl,
11.59 (%). Found: C, 62.74; H, 6.46; N, 13.54; Cl, 11.61 (%).
EXAMPLE 6
(1) A mixture of cyclohexene oxide (Va) (9.81 g), ethanol (25 ml) and
imidazole (13.6 g) was refluxed under heating for 70 hours. The ethanol
was evaporated and after addition of a small amount of water, the residue
was extracted with chloroform. The extract was washed with a small amount
of water, dried and evaporated to give 2-imidazolylcyclohexanol (IVa)
(12.7 g) as crystaline residue (Yield 76%). Mp. 133.degree.-134.degree. C.
NMR: .delta.(CDCl.sub.3) 1.3-2.2m 8H, 3.6m 2H, 4.86s 1H, 6.83s 1H, 6.89s
1H, 7.30s 1H.
(2) By the treatment in the same manner as in Example 5(2),
2-imidazolylcyclohexanone (IIa) was obtained (yield 17%). Mp.
104.degree.-105.degree. C.
IR: .nu..sub.max (CHCl.sub.3) 1730 cm.sup.-1.
NMR: .delta.(CDCl.sub.3) 1.6-2.7m 8H, 4.78d-d (J=12, 4) 1H, 6, 9s 1H, 7.1s
1H, 7.46s 1H.
(3) To a Grignard reagent prepared from anhydrous THF (4 ml), magnesium (41
mg) and 2-bromothiophene (0.18 ml) was added dropwise a solution of
Compound IIa (185 mg) in THF (6 ml) at room temperature. The mixture was
refluxed under heating for 1 hour. After evaporation of the solvent
followed by addition of water, the residue was extracted with chloroform.
The extract was washed with water and evaporated. The residue was applied
to column chromatography on silica gel (5 g). From the chloroform-methanol
(50:1) fraction, cis-1-(2-thienyl)-2-imidazolylcyclohexanol (6) (238 mg)
was obtained (yield 85%). Mp. 82.degree.-84.degree. C. (ether).
NMR: .delta.(CDCl.sub.3) 1.7-2.4 (br) 8H, 3.92d-d (J=12, 4) 1H, 4.15 (br)
1H, 6.6-7.1m 6H.
EXAMPLES 7-10
The following compounds were obtained in the same manner as in the above
Examples.
TABLE 10
______________________________________
##STR6##
Example
No. R n Y Mp (.degree.C.)
NMR: .delta. (CDCl.sub.3)
______________________________________
7 2-chloro-
2 N 163-5 4.28d-d(J=12, 4)3.73s
benzyl
8 2-thienyl
2 N 131-2 4.40d-d(J=11, 4)5.05s
9 2-thienyl
3 N 135-6 4.45d-d(J=11, -1)5.1s
10 ethyl 2 N 62-3 4.20d-d(J=12, 4)3.67s
______________________________________
EXAMPLE 11
To a solution of cis-1-(2-thienyl)-2-(1,2,4-triazol-1-yl)cyclohexanol (8)
(1.42 g) obtained in Example 8 in methylene chloride (20 ml) was added
dropwise 1.81M chlorine-carbon tetrachloride solution (7.9 ml) with
stirring under ice-cooling. The mixture was made to react at room
temperature for 30 minutes. After addition of an aqueous solution of
sodium hydrogencarbonate, the reaction mixture was extracted with
methylene chloride. The extract was washed with water, dried and
evaporated. The residue was chromatographed on Lober column (Trademark,
Merck & Co., Ltd.) and eluted.
From the early fractions,
cis-1-(3,4,5-trichloro-2-thienyl)-2-(1,2,4-triazol-1-yl)cyclohexanol (12)
(220 mg). Mp. 199.degree.-199.5.degree. C. (acetone-ether).
NMR: .delta.(CDCl.sub.3) 5.23d-d (J=12, 4) 1H, 5.80s 1H.
Successively,
cis-1-(3,5-dichloro-2-thienyl)-2-(1,2,4-triazolyl-1-yl)cyclohexanol (11)
(380 mg) was obtained. Mp. 174.degree.-175.degree. C. (acetone-ether).
NMR: .delta.(CDCl.sub.3) 5.22d-d (J=12, 4) 1H, 5.67s 1H.
From the latter fractions,
cis-1-(5-chloro-2-thienyl)-2-(1,2,4-triazol-1-yl)cyclohexanol (4) (560 mg)
was obtained. Mp. 152.degree.-153.degree. C. (ether-hexane).
NMR: .delta.(CDCl.sub.3) 4.4d-d (J=12, 4) 1H, 5.17s 1H.
EXAMPLE 12
A solution of cis-1-(2-thienyl)-2-(1,2,4-triazol-1-yl)cycloheptanol (9)
(790 mg) obtained in Example 9 in methylene chloride (25 ml) was added
1.8M chlorine-carbon tetrachloride solution (2.5 ml) under ice-cooling.
The mixture was made to react for 10 minutes. After addition of a sodium
hydrogencarbonate solution, the mixture was extracted with methylene
chloride. The extract was washed with water and evaporated. The residue
was applied to column chromatography on silica gel (15 g). From the ether
fraction, cis-1-(5-chloro-2-thienyl)-2-(1,2,4-triazol-1-yl)cycloheptanol
(13) (585 mg) was obtained. Mp. 170.degree.-173.degree. C.
NMR: .delta.(CDCl.sub.3) 4.38d-d (J=11, -1) 1H, 5.13s 1H.
EXAMPLE 13
(1) To a Grignard reagent prepared from magnesium (26.7 g),
2,5-dichlorothiophene (16.83 g) and anhydrous THF (70 ml) was added
dropwise in small portions a solution of cyclohexanone (XIa) (9.815 g) in
anhydrous THF (30 ml) with stirring under ice-cooling in nitrogen
atmosphere. The mixture was made to react at room temperature for 3 hours
and after addition of water and acidification with 5% hydrochloric acid,
extracted with chloroform. The extract was washed with water, dried and
evaporated. The residue was applied to column chromatography on silica gel
(70 g). From the benzene fraction, 1-(5-chloro-2-thienyl)cyclohexanol (Xa)
(17.6 g) was obtained as an oil (yield 81.2%).
(2) To a solution of Compound Xa (17.6 g) in toluene (300 ml) was added
p-toluenesulfonic acid (500 mg). The resulting water was removed by
azeotropic evaporation. The residual solution was cooled, washed with a 5%
aqueous solution of potassium carbonate and water successively and
evaporated to give 1-(5-chloro-2-thienyl)cyclohexene (IXa) (16.0 g) as an
oil.
NMR: .delta.(CDCl.sub.3) 1.67m 4H, 2.25 (Br) 4H, 6.00 (Br) t-like 1H, 6.43d
(J-4) 1H, 6.72d (J-4) 1H.
(3) The above Compound IXa (7.0 g) was dissolved in a mixture of acetone
(130 ml) and water (20 ml) and thereto added N-bromoacetamide (5.84 g).
After stirring at room temperature for 2.5 hours followed by addition of
water and a 1% aqueous solution of sodium thiosulfate, the mixture was
extracted with chloroform. The extract was washed with water and
evaporated to give tran-1-(5-chlorothienyl)-2-bromocyclohexanol (VIIa), as
colored oily residue. The residue was dissolved in dimethylacetamide (20
ml) and the solution was added to a solution of sodium triazole prepared
from 1,2,4-triazole (4.87 g), dimethylacetamide (30 ml) and 60% sodium
hydride (2.11 g). The mixture was made to react at 100.degree. C. for 6
hours and then kept at room temperature for 3 days. After addition of
water, the reaction mixture was extracted with ethyl acetate. The extract
was washed with water, dried and evaporated. The residue was applied to
column chromatography on silica gel (150 g). From the ether fraction
crystalline residue (5.53 g) was obtained. The product was recrystallized
from ether to give
trans-1-(5-chloro-2-thienyl)-2-(1,2,4-triazol-1-yl)cyclohexanol (14) (2.1
g) (mp. 167.degree.-170.degree. C.). Recrystallization from acetone gave
Compound 14 (1.75 g) melting at 170.degree.-172.degree. C.
Anal. Cacld. for C.sub.12 H.sub.14 N.sub.3 OSCl: C, 50.79; H, 4.97; N,
14.81; S, 11.30; Cl, 12.49 (%). Found: C, 50.53; H, 4.97; N, 14.67; S,
11.21; Cl, 12.72 (%).
NMR: .delta.(CDCl.sub.3) 1.6-2.5m 8H, 4.43d-d (J=9, 5) 1H, 5.07s 1H, 6.45d
(J=4) 1H, 6.63d (J=4) 1H, 7.9s 2H.
EXAMPLE 14
Five parts of Compound 1, 20 parts of propylene alcohol, 5 parts of
polyoxyethylene alkyl phenyl ether and 70 parts of water are mixed and
dissolved to give a solution, which is diluted so that the effective
concentration of Compound 1 is 10-500 ppm and sprayed foliary. (The number
of the compound corresponds to that used in the example for preparation.
The same will be applied hereinafter.)
EXAMPLE 15
A solution is prepared in the same manner as in Example 14 using Compound 3
instead of Compound 1.
EXAMPLE 16
One part of Compound 5 is mixed with 99 parts of talc to give a dust.
EXAMPLE 17
Twenty-five parts of Compound 6, 8 parts of polyoxyethylene alkyl phenyl
ether, 2 parts of sodium alkylbenzenesulfonate and 65 parts of xylene are
mixed and dissolved to give a concentrated emulsion, which is diluted so
that the effective concentration of Compound 6 is 50-500 ppm and sprayed
foliarly.
EXAMPLE 18
Five parts of Compound 12, 90 parts of an equal-weight mixture of bentonite
and talc and 5 parts of sodium alkylbenzenesulfonate are mixed, crushed
and formulated to granules.
EXAMPLE 19
Fifty parts of Compound 13, 6 parts of sodium alkylbenzene sulfonate, 4
parts of sodium lignine sulfonate and 40 parts of clay are mixed and
crushed to give a wettable powder, which is diluted so that the effective
concentration of Compound 13 is 10-500 ppm and sprayed to fruit.
EXAMPLE 20
A wettable powder is prepared in the same manner as in Example 19 using
Compound 14 instead of Compound 13.
EXAMPLE 21
(1) A mixture of cyclohexene oxide (Va) (9.81 g), ethanol (25 ml) and
imidazole (13.6 g) was refluxed under heating for 70 hours and the ethanol
is removed by evaporation. After addition of a small amount of water, the
residue was extracted with chloroform. The extract was washed with a
saturated aqueous solution of sodium chloride, dried and evaporated to
give 2-imidazolylcyclohexanol (IVa) (12.7 g) as crystaline residue (yield
76%). Mp. 133.degree.-134.degree. C. NMR: .delta. (CDCl.sub.3) 1.3-2.2m8H,
3.6m2H, 4.86s1H, 6.83s1H, 6.89s1H, 7.30s1H ppm.
(2) Dimethylsulfoxide (8.46 g) was mixed with methylene chloride (35 ml)
and cooled to -76.degree. C. with stirring and after dropwise addition of
a diluted solution of trifluoroacetic anhydride (19.71 g) in methylene
chloride (10 ml), stirred for 1 hour. A solution of of
2-imidazolylcyclohexanol (IVa) (12.0 g) in methylene chloride (100 ml) was
added dropwise thereto for 10 minutes. The mixture was made to react at
-76.degree.--20.degree. C. for 1.5 hours, cooled to -55.degree. C. and
after dropwise addition of triethylamine (30 ml) at -55.degree. C.,
stirred for 1 hour at -55.degree. C. After addition of a 5% sodium
hydroxide solution, the mixture was extracted with methylene chloride. The
extract was washed with water, dried and evaporated. The residue was
applied to column chromatography on slica gel (100 g). From
Chloroform-methanol (100:1) fraction, 2-imidazolyl cyclohexanone (IIa)
(2.3 g) was obtained. Mp. 104.degree.-105.degree. C.
IR: .nu..sub.max (CHCl.sub.3) 1730 cm.sup.-1
(3) To a Grignard reagent prepared from magnesium (58 mg),
3,4-dichlorobromobenzene (537 mg) and THF (6 ml) was added dropwise a
solution of Compound IIa (260 mg) in THF (10 ml). The mixture was refluxed
for 1 hour, acidifid with 5% hydrochloric acid, made alkaline with 5%
potassium carbonate and extracted with chloroform. The extract was washed
with water and evaporated. The residue was applied to column
chromatography on silica gel (6 g). From chloroform-methanol (50:1)
fraction, cis-1-(3,4-chlorophenyl)-2-imidazolylcyclohexanol (21) (225 mg)
was obtained (yield 46%), Mp. 198.degree.-199.degree. C. (acetone-ether).
Anal. calcd. for C.sub.15 H.sub.16 N.sub.2 OCl.sub.2 : C, 57.89; H,5.18;
N,9.00; Cl,22.78 (%). Found: C,58.02; H,5.21; N,8.92; Cl,22.86 (%).
NMR: .delta. (CDCl.sub.3) 1.7-2.5m8H, 3.98d-d(J=12,4)1H, 6.72br2H,
7-7.36m4H ppm.
EXAMPLE 22
To a Grignard reagent prepared from anhydrous THF (30 ml), magnesium (880
mg) and p-chlorobromobenzene (6.95 g) was added dropwise a solution of
2-(1,2,4-triazol-1-yl)cyclohexanone (IIb) (5.0 g) in THF (35 ml) at room
temperature with stirring. The mixture was made to react at room
temperature for 2 hours and the solvent was removed by evaporation. After
addition of water, the residue was extracted with chloroform. The extract
was washed with water, dried and evaporated. The residue was applied to
column chromatography on silica gel (80 g). From chroloform-methanol
(100:1) fraction,
cis-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)cyclohexanol (5.21 g) was
obtained as crystal (yield 62%). Mp. 128.degree.-130.degree. C.
(ether-hexane).
NMR: .delta. (CDCl.sub.3) 1.6-2.6br8H, 4.52d-d(J=12, 4)1H, 4.95s1H,
7.17s4H, 7.68s1H, 7.8s1H ppm.
EXAMPLE 23
(1) To a solution of cycloheptene (VII) (10 g) in methylene chloride (400
ml) was added 85% m-chloroperbenzoic acid (23 g) in small portions with
stirring under ice-cooling. The mixture was made to react at
3.degree.-10.degree. C. for 10 hours and at room temperature for 3 hours
and after removal of the precipitated benzoic acid by filtration, washed
with methylene chloride. The filtrate and the washings were combined and
washed with an aqueous solution of sodium thiosulfate, 5% potassium
carbonate and water successively, dried and evaporated to give
cycloheptene oxide (Vb).
A mixture of the product, propanol (30 ml) and imidazole (8.5 g) was
refluxed for 20 hour under heating and the propanol was removed by
evaporation. After addition of a small amount of water, the reaction
mixture was extracted with chloroform. The extract was washed with a
saturated aqueous solution of sodium chloride, dried and evaporated to
give an oily residue. The residue was applied to column chromatography on
silica gel (60 g). From chloroform fraction, the starting material (4.41
g) was recovered and from chloroform-methanol (50:1) fraction,
trans-2-imidazolylcycloheptanol (IVc) (3.96 g) was obtained as an oil
(yield 21%).
NMR: .delta. (CDCl.sub.3) 1.73n10H, 2.12br2H, 5.27s1H, 6.77s1H, 6.83s1H,
7.27s1H ppm.
(2) Dimethylsulfoxide (2.57 g) was mixed with methylene chloride (20 ml),
cooled to -76.degree. C. with stirring, wherein a diluted solution of
anhydrous trifluoroacetic acid (6.0 g) in methylene chloride (10 ml) was
added dropwise. The mixture was stirred for 1.5 hours under cooling and a
solution of Compound IVc (3.96 g) in methylene chloride (25 ml) was added
dropwise. The mixture was made to react at -76.degree.-0.degree. C. for 1
hour, cooled to -60.degree. C. and after dropwise addition of
triethylamine (9 ml), stirred for 1 hour at -60.degree.-5.degree. C. Water
was added to the reaction mixture. The mixture was made alkaline with 5%
sodium hydroxide and extracted with methylene chloride. The extract was
washed with water, dried and evaporated. The residue was applied to column
chromatography on silica gel (40 g). From chloroform-methanol fraction
(100:1), 2-imidazolylcycloheptanone (IIc) (0.77 g) was obtained. Mp.
68.degree.- 69.degree. C.
IR: .nu..sub.max (CHCl.sub.3) 1720 cm.sup.-1
NMR: .delta. (CDCl.sub.3) 1.4-2.2m8H, 2.57m2H, 4.97d-d(J=8, 5)1H,
6.85d(J=1)1H, 7.38d(J=1)1H ppm.
(3) To a solution of Grignard reagent prepared from anhydrous THF (6 ml),
magnesium (45 mg) and p-fluorobromobenzene (200 mg) was added dropwise a
solution of Compound IIc (200 mg) prepared in the above (2) in THF (8 ml)
under refluxing. The mixture was refluxed for 1 hour with stirring and
then evaporated. After addition of water, the residue was extracted with
chloroform. The extract was washed with water, dried and evaporated. The
residue was applied to column chromatography on silica gel (6 gl). From
chloroform-methanol (50:1) fraction,
cis-1-(4-fluorophenyl)-2-imidazolylcycloheptanol (23) (180 mg) was
obtained as crystal Mp. 164.degree.-165.degree. C.
NMR: .delta. (CDCl.sub.3) 1.7-2.6m10H, 3.98d-d(J=11, 2)1H, 3.9br1H,
6.63brs2H, 6.7-7.2m5H ppm.
EXAMPLE 24
(1) Cycloheptene oxide (Vb) prepared from cycloheptene (10 g) in the same
manner as in Example 23(1), propanol (25 ml) and 1,2,4-triazole (8.6 g)
were made to react at 100.degree. C. for 4 hours and the propanol was
removed by evaporation. After addition of a small amount of water, the
reaction mixture was extracted with chloroform. The residue was washed
with a saturated aqueous solution of sodium chloride, dried and
evaporated. The residue was recrystallized from ether-hexane to give
2-(1,2,4-triazole-1-yl)cycloheptanol (IVd) (13.3 g) melting at
85.degree.-86.degree. C. (yield 35.8%).
NMR: .delta. (CDCl.sub.3) 1.6-2m10H, 4br2H, 5.0s1H, 7.73s1H, 8.03s1H ppm.
(2) A solution of dimethylsulfoxide (1.05 g) in methylene chloride (10 ml)
was cooled to -78.degree. C. and a solution of trifluoroacetic anhydride
(1.65 ml) in methylene chloride (4 ml) was added dropwise thereto with
stirring. The mixture was stirred for 1 hour under cooling. A solution of
Compound IVd (1.63 g) in methylene chloride (18 ml) was added dropwise
thereto. The mixture was made to react at -76.degree.-10.degree. C. for
1.5 hours, after cooling to -65.degree. C., mixed with triethylamine (3.75
ml) and stirred at -65.degree.-0.degree. C. for 1 hour. The reaction
mixture was made alkaline with 5% potassium hydroxide and extracted with
methylene chloride. The residue was washed with water, dried and
evaporated. The residue was applied to column chromatography on silica gel
(30 g). From chloroform-methanol (100:1) fraction,
1-(1,2,4-triazol-1-yl)cycloheptanone (IId) (1.16 g) was obtained (yield
72%). Mp. 82.degree.-82.5.degree. C. (ether-hexane).
IR: .nu..sub.max (CHCl.sub.3) 1720 cm.sup.-1
NMR: .delta. (CDCl.sub.3) 1.5-2.3m8H, 2.65m2H, 5.28d-d (J=12, 5)1H,
7.91s1H, 8.22s1H ppm.
(3) To a Grignard reagent prepared from anhydrous THF (20 ml), magnesium
(835 mg) and p-chlorobromobenzene (6.57 g) was added dropwise a solution
of Compound IId (4.1 g) in THF (35 ml) under cooling. The mixture was made
to react at room temperature for 1 hour, after addition of water,
acidified with 5% hydrochloric acid, made alkaline with 5% potassium
carbonate solution and then extracted with benzene. The extract was washed
with water, dried and evaporated. The residue was applied to column
chromatography on silica gel (70 g). From the ether fraction,
cis-1-(4-chlorophenyl)-2-(1,2,4-triazol-1-yl)cycloheptanol (24) (3.6 g)
was obtained as crystals (yield 54%). Mp. 129.degree.-131.degree. C.
(acetone-hexane).
Anal. calcd. for C.sub.15 H.sub.18 N.sub.3 OCl: C,61.75; H,6.22; N,14.40;
Cl,12.15 (%). Found: C,61.71; H,6.22; N,14.31; Cl12.45 (%).
EXAMPLES 25-35
The following compounds were obtained by the same procedure as in the above
examples.
TABLE 11
__________________________________________________________________________
##STR7##
Example NMR: .delta. (CDCl.sub.3 J=Hz
No R n Y Mp (.degree.C.)
H.sub.A OH
__________________________________________________________________________
25 Phenyl 2 N 147-8 4.52d-d(J=12, 4)
4.83s
26 4-Chlorophenyl
2 CH
171-3 3.96d-d(J=12, 4)
4.0(Broad)
27 4-Chlorophenyl
3 CH
163-4 4.0d-d(J=11, 2)
3.6(broad)
28 4-Fluorophenyl
2 N 112-3 4.40d-d(J=12, 4)
4.87s
29 4-Fluorophenyl
2 CH
183-4 3.92d-d(J=12, 4)
5.2s
30 4-Fluorophenyl
3 N 152-3 3.98d-d(J=11, -1)
3.9(broad)
31 3-Chlorophenyl
2 N 154-7 4.60d-d(J=12, 4)
4.87s
32 2-Chloropheny
2 N 142-3 5.70d-d(J=12, 4)
5.0s
33 3,4-Dichlorophenyl
2 N 158-160
4.52d-d(J=12, 4)
5.0s
34 3,4-Dichlorophenyl
3 N 178-9 4.50d-d(J=11, -1)
4.96s
35 2,5-Dichlorophenyl
2 N 221-2 5.45d-d(J=12, 4)
5.93s
__________________________________________________________________________
EXAMPLE 36
Five parts of Compound 22, 20 parts of propylene alcohol, 5 parts of
polyethylene alkyl phenyl ether and 70 parts of water are mixed and
dissolved to give a solution, which is diluted with water so that the
effective concentration of Compound 22 is 50-500 ppm, and sprayed
foliarly.
EXAMPLE 37
Fifty parts of Compound 24, 6 parts of sodum alkyl benzenesulfonate, 4
parts of sodium lignine sulfonate and 40 parts of clay are mixed and
crushed to give a wettable powder, which is diluted so that the effective
concentration of Compound 24 is 50-500 ppm, and sprayed on fruit.
EXAMPLE 38
Five parts of Compound 28, 90 parts of an equal-weight mixture of bentonite
and talc and 5 parts of sodium alkyl benzenesulfonate are mixed, crushed
and formulated to granules.
EXAMPLE 39
Twenty-five parts of Compound 30, 8 parts of polyoxyethylene alkyl phenyl
ether, 2 parts of sodium alkyl benzenesulfonate and 65 parts of xylene are
mixed and disslved to give a concentrated emulsion, which is diluted so
that the effective concentration of Compound 30 is 50-5000 ppm and sprayed
foliarly.
EXAMPLE 40
One part of Compound 1 is mixed with 99 parts of talc to give a dust.
EXAMPLE 41
A solution is prepared in the same manner as in Example 36 using Compound
33 instead of Compound 22.
EXAMPLE 42
A wettable powder is prepared in the same manner as in Example 37 using
Compound 34 instead of Compound 24.
EXAMPLE 43
Granules are prepared in the same manner as in Example 38 using Compound 35
instead of Compound 28.
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